Pemphigus forms and target antigens.
\r\n\tIt is believed that deterioration in structures are needed to be linked with risk management in construction. Faulty of construction directly affect to the deterioration. Therefore, second part of this book considers the lessons learned in construction management. Project and site managers, quality engineers are most welcome to discuss the reasons of deteriorated structures through project planning to the serviceability of such structures.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"c25011195dc649bb9b63d88c55c2f706",bookSignature:"Dr. Hakan Yalciner",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7450.jpg",keywords:"Structures, deterioration, seismic performance,monitoring techniques, serviceability of structures,repair and strengthening methods, scoring of structures, material degradation, environmental effects, time dependent effects, risk management, lessons learned, construction management",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 27th 2018",dateEndSecondStepPublish:"April 17th 2018",dateEndThirdStepPublish:"June 16th 2018",dateEndFourthStepPublish:"September 4th 2018",dateEndFifthStepPublish:"November 3rd 2018",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"72283",title:"Dr.",name:"Dr. Hakan",middleName:null,surname:"Yalciner",slug:"dr.-hakan-yalciner",fullName:"Dr. Hakan Yalciner",profilePictureURL:"https://mts.intechopen.com/storage/users/72283/images/system/72283.jpeg",biography:"Associate Professor Dr. Hakan Yalciner is an earthquake and structure engineer in Erzincan Binali Yıldırım University and chair in the Department of Civil Engineering. Dr. Hakan Yalciner received his PhD from Eastern Mediterranean University. He is a voting member of ACI Committees 546-00 (Repair of Concrete) and 546-0E (Corrosion Studies). His research interests include performance analysis of structures under extreme conditions and loads, such as corrosion, seismic events, and blast. Dr. Yalciner developed different empirical models for the prediction of the structural behavior of corroded reinforced concrete members. He is currently director of the 13th March of Structural Mechanics Laboratory in Erzincan Binali Yıldırım University. His total accepted budget for academic projects in 2018 was US$250,000.\nwebsite: https://drhakanofficials.info/",institutionString:"Erzincan University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Erzincan University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6957",title:"New Trends in Structural Engineering",subtitle:null,isOpenForSubmission:!1,hash:"8c26eaf65a25f29d43abd17ff651746f",slug:"new-trends-in-structural-engineering",bookSignature:"Hakan Yalciner and Ehsan Noroozinejad Farsangi",coverURL:"https://cdn.intechopen.com/books/images_new/6957.jpg",editedByType:"Edited by",editors:[{id:"72283",title:"Dr.",name:"Dr. Hakan",surname:"Yalciner",slug:"dr.-hakan-yalciner",fullName:"Dr. Hakan Yalciner"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"60009",title:"Introduction to Autoimmune Bullous Diseases",doi:"10.5772/intechopen.75392",slug:"introduction-to-autoimmune-bullous-diseases",body:'\nBullae are formed as a result of the damage of skin integrity due to various reasons, including bacterial or viral infections, trauma, genetic disorders and autoantibodies and fluid accumulation in the different layers of the skin; subcorneal, suprabasilar, dermal-epidermal junction and upper dermis [1]. Autoimmune bullous diseases (ABD) are a heterogeneous group of rare but fatal or debilitating skin diseases characterized by varying degrees of mucosal and cutaneous blister formation due to autoantibodies directed against the structural proteins of epidermis or the dermal-epidermal junction [2, 3]. ABD are classified according to the location of the bullae in the skin and the antigens targeted by the antibodies. They are simply examined in four main groups: pemphigus, pemphigoid, acquired epidermolysis bullosa and dermatitis herpetiformis [1].
\nIt is important to know the structure of the skin and antigens targeted by autoantibodies in order to better understand the ABD. The epidermal stratified squamous epithelium is a complex structure which includes several layers of keratinocytes. Cohesion among these cells is needed to preserve the epidermal architecture and function [4]. Epidermal integrity is provided by three types of junctional structures: (1) anchoring junctions (desmosomes and adherens junctions), major adhesive cell–cell junctions of epithelial cells that function with each other to hold epithelial sheets together. Both are connected with the cytoskeleton and represent sites of mechanical coupling between cells. (2) Tight junctions (zonula occludens) that constitute a diffusion barrier. (3) Gap junctions, where intercellular channels allowing for the direct exchange of small molecules between cells [4, 5]. While suprabasal, differentiating keratinocytes adhere to each other, undifferentiated basal keratinocytes are anchored to the dermis and interact with extracellular matrix. Basal cell surfaces not in contact with basement membrane have desmosomes which attach adjacent keratinocytes [1].
\nDesmosomes are disc-like strong cell–cell adhesion complexes that act as anchors linking the intermediate filament (IF) cytoskeletons of neighboring cells in tissues that undergo large amounts of mechanical strain such as the heart and skin [6, 7]. In addition to their adhesive role, desmosomes are dynamic structures that regulate normal physiological processes such as proliferation and differentiation during development, tissue morphogenesis and wound healing [3, 6, 8–10].
\nDesmosomes are described as small dense nodules at the contact points between neighboring cells. “Desmos” means “bond” and “soma” means “body.” Electron microscopic investigations and newly developed procedures have supplied detailed knowledge about their structures and major protein components [3].
\nDesmosomes are 0.2–0.5 μm in diameter in human epidermis and consist of dense plaques located symmetrically on the plasma membranes of adjoining cells. Extracellular domain, a dense midline separates the membranes [8, 11].
\nDesmosomes, calcium-dependent junctions, have five major component proteins such as the desmosomal cadherins (DCs) [desmoglein (dsg) and desmocollin (dsc)], the plakin family [desmoplakins, (DP)], and the armadillo proteins [plakoglobin (PK) and plakophilin (PP)] [6, 8].
\nDsg and dsc are desmosomal adhesion molecules, and there are four dsg (1–4) and three dsc (1–3) in different tissues in humans. Dsg2 and dsc2 are present in all tissues that contain desmosomes such as simple epithelia, myocardium and are present in low amounts in basal layer of complex epithelia like epidermis [4, 6]. While dsg4 is present in both stratified epithelia and hair, dsg1/3 and dsc1/3 are found only in stratified epithelia. Dysregulation of desmosomal cadherins causes skin, hair, heart and digestive tract disorders and cancer because of their roles in epithelial morphogenesis and differentiation [6].
\nExtracellular domains of dsg and dsc are highly homologous to those of classical cadherin, E-cadherin, which have five extracellular cadherin repeats containing Ca2+ binding sites and a cell-adhesion recognition (CAR) site [4, 8]. The cytoplasmic domains of dsg have a membrane proximal region, including an intracellular cadherin-typical region and a dsg-specific region [8].
\nDsg 1 expression is higher in suprabasal layers in the skin epithelium. Dsg1 can support keratinocyte differentiation. Extracellular regions of dsg1 do not play a role in this function; they are needed for adhesion. In the recent years, mutations in dsg1 that cause severe skin dermatitis, multiple allergies and metabolic wasting syndrome (SAM) have been identified [6].
\nIn the epidermis, dsg1 and 3 show inverse distribution patterns, dsg3 is present in high levels in the basal layer but dsg1 is found in low levels in this layer. However, the upper layers have high levels of dsg1 and low levels of dsg3. Therefore, pemphigus foliaceus causes bullae only in the most superficial layers of the skin while pemphigus vulgaris leads to blisters in the basal layers of the skin. Because dsg1 and dsg3 are both found in the intermediate layers, blisters do not typically occur in these layers (compensation hypothesis) [6].
\nThe armadillo-repeat family members which are PG and the PP are characterized by their central arm-repeat domains. PG, together with PP, provides the adhesion of DP to keratin intermediate filaments and mediates important signal transduction pathways and regulates the clustering of desmosomal components [12].
\nİ. Plakoglobin: PG has three structural components as an N-terminal and a C-terminal domain which are separated by the central 12 arm-repeat domain and is homologous to b-catenin. Despite this homology, PG and b-catenin are differently distributed at cell–cell contacts. b-catenin normally is not a component of desmosomes and is only present in adherens junctions unlike PG [5]. PG plays an important role in heart, skin and hair development. Pg−/− mice show severe cardiac defects and Naxos disease that presents with arrhythmogenic right ventricular cardiomyopathy, wooly hair and keratoderma due to the mutation in the gene encoding PG [8].
\nii. Plakophilins: PP are members of armadillo-repeat family, and PP1 was originally isolated as an accessory desmosomal plaque protein in stratified and complex epithelia binding to keratin. Later, PP2 and 3 and their subtypes were defined. PP are present both at desmosomes and in the nucleus [5]. While PP1 is mostly expressed in the suprabasal layer, PP2 is located in lower layers of stratified epithelia and heart [12]. All PP have diverse biological and pathological roles [6]. PP1 has an important role in desmosomal plaque formation and stability. PP1 mutation causes ectodermal dysplasia-skin fragility syndrome in which skin fragility, inflammation, ectodermal development abnormalities such as scant hair, hypohidrosis and astigmatism are seen [8]. Also, PP1 is elevated in the head and neck cancers and Ewing sarcoma. Therefore, it has been thought that PP1 regulates cell proliferation and growth.
\nPP2 has a role in the regulation of actin cytoskeletal dynamics, cell migration and tumorigenesis in addition to modulation of intercellular adhesion. PP2 is a new positive regulator for EGFR activation. Knockdown of PP2 causes the attenuation of EGFR-mediated signals and tumor development [6].
\nAlso, the mutations in PP2 have been identified as a cause of arrhythmogenic right ventricular cardiomyopathy.
\nPP3 mutations have not yet been identified in humans but pp3 deficient mice developed cutaneous inflammation and hair abnormalities [8]. This protein mRNA expression has been found to be significantly higher in gastrointestinal cancer patients than controls. Also, its level increased in advanced stages and metastatic cancer. Moreover, it was found that PP3 was increased in breast and pancreatic cancers [6].
\nPlakins presents with a family of very large cytolinker proteins of 200–700 kDa. They have important role in the cross-linking of actin microfilaments, microtubules and/or intermediate filaments to each other and provide the connection of adhesive junctions with the cytoskeleton. There are seven identified plakin proteins and four of them, desmoplakin (DP), plektin, envoplakin and periplakin are localized in the desmosomes [5].
\ni. Desmoplakin: DP is an essential desmosomal component in the connection of desmosomal proteins with intermediate filament (IF) cytoskeleton. DP has a critical role in the heart and skin. Global knockout of DP in mouse causes lethality at embryonic days leading to a dramatic decrease in the desmosome numbers [6].
\nThe N-terminal plakin domain peptide (DP-NTP) is essential to target DP to desmosomal plaques and contains binding sites for PPs and PG. The carboxy terminal domain of DP is composed of three plakin repeat domains (PRDs) named A, B and C and is responsible for the attachment of IF [5, 12]. The molecular interactions within the desmosomal plaque protein network are much complicated. It has been shown that the PP1 head domain acts as a lateral linker and allows the recruitment of additional DP molecules to the desmosomal plaque. Moreover, there is evidence that DP might bind directly to desmosomal cadherins in the absence of PG and PPs. But, in cells expressing PP1 and PG, DP preferentially binds to PP1. While dsg1 is the only desmosomal cadherin that interacts with the PP1 head domain PP2 interacts directly with dsg1 and 2, and dsc1a and 2a. In contrast to PP1, PP2 binds to PG. Together with the different tissue distribution of the PPs, the different binding specificities may be involved in the regulation of the size and cadherin composition of desmosomes and the efficiency of IF binding to desmosomes [5].
\nTwo major isoforms of DP were identified: DP1 and DP2. Both are widely expressed in numerous tissues but DP2 is absent/reduced in the heart and simple epithelia [12]. The loss of DP2 causes a more severe adhesion defect due to mechanical stress [6]. DP2 has a more significant role than DP1 in maintaining the adhesion of keratinocytes [12]. Sarcoendoplasmic reticulum Ca+2-ATPase isoform 2 (SERCA2) regulates DP translocation to sites of cell–cell adhesion and SERCA2 is often mutated in Darier’s disease. If mutation in DP leads to complete loss of protein or loss of the IF-binding C terminus, it results in lethal acantholytic epidermolysis bullosa with or without apparent associated cardiomyopathy. DP missense mutation can lead to Carvajal/Naxos syndrome that is characterized by keratoderma, wooly hair and cardiomyopathy [6, 8]. Consequently, desmosome mutations can lead to aberrant gap junctions and abnormal heart and epidermal functions, abnormal barrier homeostasis of skin. The loss of DP may also be associated with some cancers and/or their local invasion because of the loss of desmosomal function [6].
\nii. Plectin: Plectin, a huge protein, was an originally IF-binding protein and was identified in hemidesmosomal and focal adhesion structures in the basal membrane of keratinocytes in the basal layer of the skin and striated, smooth and cardiac muscles. Later, it was shown that plectin is also expressed in desmosomes. However, it has an auxiliary role and is not a major component of desmosomes. It has major function in the organization of microtubules, actin and IF by coordinated cross-linking and the regulation of their dynamics. Plectin gene mutation does not cause blistering in the epidermis but cause blister formation in the epidermal basal layer by affecting hemidesmosomes. Plectin gene mutation causes autosomal recessive epidermolysis bullosa simplex (EBS) associated with muscular dystrophy [5].
\niii. Envoplakin: Envoplakin was originally identified as a plakin protein family member. It was found along IFs and is partially colocalized with DP at desmosomes in terminally differentiating keratinocytes. Similar to plectin, envoplakin is not a major component of desmosomes. Envoplakin knockout mice normally develop but they have only a slight delay in barrier acquisition. No disorders due to the envoplakin mutations have been defined in humans yet [5].
\niv. Periplakin: Similar to envoplakin, periplakin is upregulated during terminal differentiation of keratinocytes in cornified envelope. It is distributed more extensively than envoplakin, but there is little knowledge about its role in other tissues. Plectin, envoplakin and periplakin play a role as auxiliary factors in strengthening IF attachment to desmosomes at the desmosomal plaque [5].
\nData have shown that adhesive binding between dsc2 and 3 and dsg2 and 3 are both homophilic and isoform specific. Dsg3 can mediate weak homophilic adhesion. Dsc3 shows homophilic binding. While there is a heterophilic interaction between dsc3 and dsg1, there is no interaction between dsc3 and dsg3 [8].
\nHyperadhesion, a strongly adhesive state is a distinctive property of desmosomes from other intercellular junctions. Adoption of hyperadhesion is a property of dsc. Keratinocytes proliferate in low Ca2+ medium but do not contact adjacent cells. At the early stage of desmosomal development, desmosomal adhesion is Ca2+ −dependent, and chelating agents may induce the loss of adhesion and splitting of desmosomes. A rise in Ca2+ concentration induces assembly of AJ and desmosomes and in the late stage, epithelial desmosome becomes resistant to low Ca2+, and hyperadhesion is characterized by Ca2+ independence [5]. Hyperadhesion is associated with the ordered arrangement of the dsc. Phosphokinase (PK) Ca may regulate Ca2+ dependence and inhibit hyperadhesion. Phosphorylation of desmosomal plaque components or different cytoplasmic signals may cause rearrangement in the plaque and transmit a signal to EC domains [8].
\nThe cell–cell contact and specific adhesive interaction are essential components for desmosome assembly. Any disorders of these components caused by low extracellular Ca2+, antibodies and blocking peptide inhibit desmosomal assembly. It was shown that intercellular adhesion starts in AJ and then stabilized by desmosomes. Antibodies to E and P cadherin block AJ and also inhibit desmosome formation [5]. PG plays an essential role in desmosomal assembly by providing interaction between AJ and desmosomes (cross-talk). Other components of desmosomal assembly are PP, dsc, dsg and DP [5, 8]. However, desmosomal assembly can also be induced by protein kinase C signaling in case of lacking of AJ. In the first step, dsg3 is transported to the cell surface, and in the second step, IF attached and half-desmosome-like structures are developed and they intermediate desmosome formation. If half desmosomes are not finally stabilized by interactions with half desmosomes on the adjacent cells they undergo endocytosis and degrade [5].
\nThe role of desmosomes in maintaining tissue integrity is defined by the large number of diseases in which one or more of its constituents are impaired [4]. The impairment of adhesive functions of desmosomal cadherins results from either development of autoantibodies against desmosomal cadherins or by gene mutations. Pemphigus is a family of blistering skin disorders caused by autoantibodies against desmosomal cadherins [5].
\nPemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two most common forms of pemphigus family and potentially fatal disorders characterized by blister formation in skin and mucous membranes (in PV) due to the acantholysis, loss of keratinocytes cell–cell adhesion. Immunochemical studies showed that in PV, autoantibodies are immunoglobulin (Ig) G type and are directed against dsg3, 130 kD glycoprotein, or both dsg3 and dsg1, 160 kD antigen [5, 13], while in PF, they directed to only dsg1 [1, 12–14]. IgG1 and 4 type autoantibodies are indicators for active disorder while IgG2 is found in remission [1, 3]. Dsg3 and dsg1 show different expression patterns throughout epidermis. Dsg1 is expressed throughout epidermis and oral mucosa but it is more predominant in superficial epidermis than in deep epidermis. In contrast, dsg3 is expressed throughout the oral mucosa but it is only present in basal and lower epidermal cells. In PF, anti-dsg IgG antibodies cause blistering in the superficial epidermis, but not in the mucosa or deep epidermis because dsg3 expression compensates loss of function due to the anti-dsg1 antibodies. In PV, anti-dsg3 antibodies cause blister development in the deepest layer of mucosa, where dsg1 expression is minimal. Mucocutaneous type PV results from both anti-dsg1 and anti-dsg3 antibodies [14–16]. But, in this type, diffuse intercellular blisters throughout epidermis do not occur. A cause of it may be that cell–cell adhesion might be weaker at the basal and intermediate suprabasal layers, where there are fewer desmosomes. Another reason may be that the lower layer of epidermis might have better access for autoantibodies which penetrate from the dermis. The main postulate of this monopathogenic theory (compensation theory) is that anti-dsg3 and 1 antibodies-dependent disabling of cell–cell adhesion is adequate to cause detachment of keratinocytes and form the blisters [3, 17]. However, data demonstrated that inactivation of dsg3 gene or depletion of dsg3 from keratinocytes could not induce gross blistering in the skin. In striate palmoplantar keratoderma which is due to N-terminal deletion of dsg1 acantholysis or skin blisters are not seen. Thus, compensation theory is still controversial [3, 15, 18]. Multipathogenic theory works to explain blister formation by multiple hit hypothesis. According to this hypothesis, a simultaneous and synchronized inactivation of physiological mechanisms of cell–cell adhesion causes disruption of epidermal detachment. Non-dsg antibodies may be pathogenic because they cause cell shrinkage, loss of adhesion at keratinocytes and/or proapoptotic signaling [17]. Additionally, IgA and IgE classes of Anti-dsg3 antibodies have been found in the sera of PV patients [3].
\nT-helper cells have critical role in the formation of pemphigus autoantibodies. Activation of autoreactive T cells (losing self-tolerance to dsg) responsive to pemphigus antigens lead to induction of IgG antibodies from B cells [3, 19]. Autoimmunity to certain epitopes of dsg3, dsg-reactive T and B cells may be seen in normal individuals particularly, the relatives of PV patients. There are dsg3 reactive Th1 cells in healthy relatives but there are Th2 cells in PV patients. Th2 reactive cells are detected at similar frequencies in the acute, chronic active and remittent phases of the disease but Th1 cells are increased in chronic active PV. It was demonstrated that Treg cells were decreased in the serum of PV patients [3, 18]. However, there is no decrease in Treg cells in PV skin lesions because Treg cells accumulate in the skin lesions and the draining lymph nodes. It has been thought that pemphigus autoimmunity can be triggered by Toll-like receptors (TLR) because of the activation of PF by TLR7 agonist, imiquimod [3].
\nIt was shown that the number and size of desmogleins are reduced in PV and PF [19]. Data demonstrated that pemphigus autoantibodies bind to conformational epitopes formed by the N-terminal 161 amino acids and stabilized by calcium on desmogleins, and that these binding areas are responsible for the pathogenicity but C-terminal extracellular domain is not the pathogenic domain [14]. Previous data showed that PV IgG most likely directly cause the loss of adhesion via the disruption of desmogleins by steric hindrance (cis or trans interaction) [12, 13, 18]. Interestingly, the detachment of keratinocytes from each other first occurs in the interdesmosomal area, and desmosomal detachment is seen in late acantholysis. Recent studies have demonstrated that the loss of desmosomal function is not only related to the steric hindrance, it may be related with other mechanisms [5, 13]. PV IgG bound to unassembled desmosomal cadherins does not prevent desmosomal generation rather, it causes internalization and degradation of IgG-antigen complex [15].
\nIt has been shown that polyclonal PV IgG causes the retraction of keratin IF and intercellular detachment in vitro in keratinocytes obtained from wild type mice. But PG has critical importance for keratin retraction and detachment of cells [14]. PV IgG binding results in the depletion of dsg3 from keratinocytes and is followed by its internalization and degradation and depriving the not yet assembled desmosome of dsg3 [12, 14]. This suggestion was supported by the demonstration of a reduction in dsg3 levels in cell lysates. In contrast, some studies showed that dsg3 levels increase in cell lysates due to the reduction of anchorage of dsg3 to the cytoskeleton caused PV IgG antibodies [15]. Recent studies in mice have not shown the loss of dsg3 in split desmosomes or keratin retraction in acantholytic areas and that dsg3 is not depleted from desmosome before acantholysis [14].
\nEarly studies showed that non-lysosomal proteases like plasminogen activator released by antibody binding caused the development of blisters but later, investigations in mice did not support this hypothesis and demonstrated that plasmin and plasminogen activators were not necessary for IgG-mediated acantholysis in mice in PV. Recent studies in vivo and in vitro have shown that selective proteases such as MMPs disrupt the adhesion of keratinocytes leading to proteolysis of adhesion molecules. While dsg3 is digested by MMP-9, a member of MMPs family, cell adhesion molecules like dsg1 and E-cadherin are digested by members of ADAM family of MMP during apoptosis [15]. In cultured keratinocytes, it has been shown that PV IgG induces apoptosis resulting in acantholysis. Apoptotic keratinocytes, reduced antiapoptotic factors and increased proapoptotic factors were detected in the epidermis in PF. Thus, induction of apoptosis may be a primary factor responsible for acantholysis and loss of intercellular adhesion. Caspases, apoptosis enzymes that have a role in acantholysis, are the other proteases. It was shown that activated caspase 3 was found in the epidermis before the blister formation, and it could cleave desmosomal proteins such as dsg1, dgs2 and dsg3. Caspases also cause the disruption of plaque proteins such as PP and DP1 and DP2, plektin and periplakin [8, 15]. Moreover, caspase inhibitors may block blister formation [8]. Shortly, these data suggested that caspases have fundamental role in apoptolysis [15]. FasL and CytC activate both extrinsic and intrinsic apoptotic signaling pathways in keratinocytes treated with PV IgGs [17]. Tumor necrosis factor alpha receptor superfamily member 5 and NADAH dehydrogenase-like protein are involved in the extrinsic and intrinsic apoptotic pathways, respectively [3].
\nAcantholysis is an active and complex process. Interaction of cell and PV IgG causes activation of phosphatidylcholine-specific phospholipase C, an increase in inositol 1,4,5 triphosphate (IP3) and diacylglycerol production and protein kinase C (PKC) activity. It also causes an increase in intracellular calcium concentration [15]. It has been shown that PV IgG causes serine-phosphorylation of dsg3, and the phosphorylation leads to the loss of PG binding. Data suggested that PG, a cytoplasmic plaque constituent, plays a critical role in keratin retraction because PG binding is essential for targeting dsg3 to desmosomes [8, 14]. Recently, a lot of protein kinase and signaling molecules, including p38 MAPK, PKC, c-myc, Src, Rho A, PERK, FAK, Akt/mTOR, and cdk2 have been demonstrated [11, 15]. For example, it was shown that p38 phosphorylation facilitates the retraction of IF and detachment of the cells [13]. Desmocollin genes encoded N-glycosylated type 1 transmembrane proteins belong to Ca-dependent cell adhesion molecules of cadherin family. Similar to dsg3, dsc3 is expressed in the basal and suprabasal layers of the epidermis. It was demonstrated that anti-dsc3 antibodies might induce the loss of adhesion of epidermal cells and contribute to blister development in pemphigus. In addition to dsg and dsc3 antibodies, reactivity to dsc1, several muscarinic and nicotinic acetylcholine receptor subtypes, HLA molecules, a number of mitochondrial proteins, thyroid peroxidase and hSPCA1 encoded ATP2C1 gene were shown. Moreover, anti-non-dsg antibodies may show the synergistic effects with anti-dsg antibodies, in other words, they may potentially amplify the activity of anti-dsg antibodies [17].
\nAnti-mitochondrial antibodies (AMA) target the mitochondrial nicotinic acetylcholine receptors that prevent apoptolysis in keratinocytes. AMA with anti-dsg antibodies can induce acantholysis, AMA/anti-dsg1 induces subcorneal splitting and AMA/anti-dsg3 induces suprabasal acantholysis. Recent studies showed that FcRn receptors exist on the keratinocytes and are a single target for PV IgG. PVIgG/FcRn complexes become internalized and are transmitted to mitochondria. Mitochondria are damaged via AMA and apoptotic signals are triggered for cell shrinkage. This shrinkage resulting in cytoskeleton collapse is an outcome of energy failure due to the damaged mitochondria [17].
\nAccording to a recent hypothesis, anti-dsg antibodies are not the reason but the result because reactivity to dsg1/3 develops in both extracellular and intracellular domains, and this gives rise to the thought that dsg molecules are released to intercellular space from damaged keratinocytes and become available to antigen presenting cells [3]. Consequently, pemphigus autoimmunity is directed to multiple organ-specific and non-organ-specific proteins.
\nParaneoplastic pemphigus (PNP) is a rare and serious form of pemphigus. It is different from other OBD because it can affect multiple organs as well as skin [11, 20]. It has unusual clinical features, including severe mucosal involvement, bronchiolitis and a wide range of skin rash (pemphigus-like, bullous pemphigoid-like, erythema multiforme-like, graft versus host disease-like and lichen planus-like) [21]. It also shows unusual histopathological and immunological findings. PNP lesions are extremely painful and may be localized on the palm and soles, conjunctiva and simple squamous epithelia. The lesions are resistant to therapy. PNP is usually associated with malignancies such as lymphoma and leukemia. The mortality rate of PNP is high (90%) [11]. It may also be associated with myasthenia gravis and thymomas [22]. Because of cutaneous and noncutaneous pathologies associated with neoplasia it is called as paraneoplastic autoimmune multiorgan syndrome [21].
\nIn PNP, targets of autoantibodies are more than one: dsgs, dscs, DP1 and 2, bullous pemphigoid antigen (BPAg)1, PF, PP, envoplakin, plectin, epiplakin and alpha-2-macroglobulin-like-1 (A2ML-1) that is a broad range protease inhibitor expressed stratified epithelia and other damaged tissues in PNP [11, 20, 22]. Characteristic autoantibodies in PNP target the plakin family proteins that are molecules localized in the intracellular plaque of desmosomes and hemidesmosomes [20]. Also, anti-acetylcholine receptor autoantibodies and acetylcholinesterase autoantibodies were detected in 35 and 28% of PNP patients, respectively. High levels of these autoantibodies correlated with dyspnea in PNP patients. These antibodies target not only epidermal proteins but also other antigens in neural and bronchial tissues [22].
\nIt is currently unclear why there are multiple autoantibodies in PNP. In patients associated with thymoma, it has been thought that defective thymocyte maturation might lead to the production of autoreactive T cells that can induce B-cell proliferation and autoantibody production. In hematologic malign tumors, aberrant immunological conditions caused by tumors might cause the production of many autoantibodies [22]. Another theory is that autoantibodies against the neoplastic antigens cross-react to epithelial antigens [21]. In PNP, responsible immunity is not solely humoral immunity, also cellular immunity plays a role in the pathogenesis. Therefore, histopathology shows individual keratinocyte necrosis with lymphocyte exocytosis in addition to deposits of autoantibodies in direct immunofluorescence (DIF) examination [20].
\nLymphoid tumors may produce antibodies to desmosome and hemidesmosome components. But this solely cannot be explained with the pathogenesis of PNP. It is thought that tumors may express proteins that cross-react with epithelial proteins such as plakins. Another mechanism is dysregulated cytokine production by the tumor cells. The levels of interleukin (IL)-6 which promotes B-cell differentiation and Ig production is increased in PNP. Epitope spreading may explain antibodies against multiple proteins found in PNP [20].
\nIn PNP, accumulation of activated CD8+ T cells and increased interferon gamma and tumor necrosis factor alpha levels were shown in the epidermis locally. Also, natural killer cells were detected in the affected tissues. Consequently, both humoral and cellular immunity play a role in the development of PNP [20].
\nAnother subtype of pemphigus is IgA pemphigus characterized by IgA antibodies to desmosomal and non-desmosomal keratinocyte cell surface constituents. It has two subtypes: subcorneal pustular dermatosis type in which there are antibodies to dsc1 and very rarely to dsc 2 and 3, and intraepidermal neutrophilic type in which target antigen is still unknown but in rare cases, anti-dsg1 and 3 antibodies are the target antigens [11, 21, 23]. The mechanism of the development of skin lesions is not clear. It is thought that IgA antibodies might bind to the Fc receptor CD89 on monocytes and granulocytes resulting neutrophil chemotaxis and subsequent proteolytic cleavage of keratinocyte cell–cell junction [21]. Recently, IgG/IgA pemphigus which is an overlapping variant of classic IgG pemphigus and IgA pemphigus has been defined. Histopathological findings are acantholysis, blister formation localized on subcorneal or entire layer of epidermis and neutrophilic infiltration [11].
\nPemphigus herpetiformis (PH) is a pemphigus form clinically resembling dermatitis herpetiformis and histopathologically pemphigus. In PH, autoantibodies against dsg1, dsg3, both dsg1 and dsg3 and more recently, dsc1, dsc3 and an unknown 178-kDa protein were recognized. PH autoantibodies may recognize functionally less important epitopes of dsg1 or 3; therefore, it does not lead acantholysis directly. It is thought that autoantibodies cause the attraction of the inflammatory cells to tissue inducing by signaling pathway of cytokine production by keratinocytes [21] (Table 1).
\nPemphigus form | \nTarget antigens | \n
---|---|
PV | \ndsg3 or dsg3 and 1, dsc1, muscarinic and, nicotinic | \n
\n | acetylcholine receptor, several HLA molecules, hSPCA | \n
\n | mitochondrial proteins, thyroid peroxidase | \n
\n | subtypes | \n
PF | \ndsg1 | \n
PH | \ndsg1, dsg3, dsc 1, dsc3, unknown 178-kDa protein | \n
PNP | \ndsgs, dscs, DP1 and 2, BPAg1, PF, PP, envoplakin, | \n
\n | plectin, epiplakin and A2ML-1 | \n
IgA pemphigus | \n\n |
SCP | \nmostly dsc1 rarely dsc2,dsc3 | \n
IEN | \nmostly unknown, some dsg1, dsg3 | \n
Pemphigus forms and target antigens.
Basement membranes are highly specialized forms of extracellular matrix composed of a distinct set of glycoproteins and proteoglycans [24]. They underlie all epithelia and endothelia, enveloping nerves, muscle fibers, distinct cell compartments and whole organs [24]. Basement membranes of various tissues differ ultrastructurally, biochemically and functionally. They act as substrates for attachment of cells, templates for tissue repair, matrices for cell migration, substratum to influence differentiation, morphogenesis and apoptosis of epithelial cell layers and permeability barriers for cells and macromolecules [25]. Basement membranes consist of lamina densa, a central electron-dense region, adjacent to a less dense area which is lamina lucida or lamina rara [24].
\nHuman skin is the body’s largest organ, which provides mechanical and immunological barrier against the external environment [26]. The interface between the lower part of the epidermis and the top layer of dermis is the dermoepidermal basement zone (BMZ) which maintains the structure and integrity of the skin by anchoring the overlying epidermis to the dermal matrix below [27]. The importance of the correct assembly of the components of BMZ for skin integrity is apparent from the multiple skin blistering disorders caused by mutations in genes coding for proteins associated with the epidermal BMZ and from autoimmune disorders where autoantibodies target these molecules. These proteins are also important in tissue homeostasis, repair and regeneration [28].
\nThe epidermal BMZ can be divided into four zones. The first zone contains the cytoskeleton, hemidesmosomes and plasma membranes of basal keratinocytes. The second zone is lamina lucida which contains filaments connecting hemidesmosomes in basal keratinocytes to the lamina densa. The third zone is lamina densa and the fourth zone is sublamina densa region which contains anchoring fibrils, anchoring plaques and fibrillin containing microfibrils [25, 29]. The biochemical components of BMZ are synthesized by basal keratinocytes and dermal fibroblasts [30]. Molecular components of epidermal BMZ are shown in Table 2.
\nCytoskeleton of basal keratinocytes | \n
Keratin 5 | \n
Keratin 14 | \n
Hemidesmosome-anchoring filament complexes | \n
Plectin | \n
230 kDa bullous pemphigoid antigen (BP230/BPAG1) | \n
Type XVII collagen (180 kDa bullous pemphigoid antigen/BP AG2) | \n
α6 ß4 integrin | \n
Tetraspan CD151 | \n
Laminin 332 | \n
Type XIII collagen | \n
Syndecans 1 and 4 | \n
α3 ß1 integrin | \n
Lamina densa | \n
Laminin 332 (formerly laminin 5) | \n
Laminin 311 (formerly laminin 6) | \n
Laminin 511(formerly laminin 10) | \n
Nidogen | \n
Type 4 collagen | \n
BM-40/SPARC | \n
Perlecan | \n
Sublamina densa region | \n
Type VII collagen | \n
Type IV collagen | \n
Elastin | \n
Fibulins | \n
Fibrillins | \n
Latent TGF-ß-binding proteins | \n
Linkin | \n
Type III collagen | \n
Type I collagen | \n
Molecular components of epidermal BMZ.
The basal keratinocytes are anchored to the basal lamina via the keratin intermediate filaments and hemidesmosomes. The molecules within the basal lamina connect the basal keratinocyte to the basal lamina which anchors the BMZ to the underlying collagenous matrix of the superficial dermis [31]. Hemidesmosomes are small, regularly spaced electron dense structures on the inner surface of the basal pole of the keratinocytes [32]. They extend from the intracellular compartment of basal keratinocytes to the lamina lucida in the upper portion of the dermal epidermal basement membrane. The intracellular domains within the basal keratinocytes attach to the keratin intermediate filament network, and within the lamina lucida, they are contiguous with anchoring filaments [30]. The anchoring filaments transverse the lamina lucida and insert it into the lamina densa. Beneath the lamina densa, the anchoring fibrils extend beneath the basement membrane within the papillary dermis. The hemidesmosomes, anchoring fibrils and anchoring filaments form the hemidesmosome-anchoring filament complex [25, 32]. The hemidesmosome-anchoring filament complex forms a continuous link between the basal keratinocyte intermediate keratin filaments and the underlying BMZ and dermal components [32, 33].
\nThere is a structural framework known as the cytoskeleton within each basal keratinocyte which is composed of three main types of filaments: microfilaments, microtubules and intermediate filaments [31]. Basal keratinocytes express intermediate filament keratins 5 and 14 which are the major keratins in the adult epidermis [32]. Intermediate filaments form an intracellular cytoskeletal network throughout the epidermis and help to maintain the cell shape and epithelial structural integrity both through the formation of a cell scaffold and through their connection to desmosomes and hemidesmosomes [27, 32]. Mutations in genes coding K5 and K14 interfere with the assembly of the tonofilament cytoskeleton and connection of intermediate filaments to desmosomes and hemidesmosomes [27]. Autosomal dominant mutations in K5 and K14 underlie epidermolysis bullosa simplex (EBS) localized to hands and feet [26].
\nPlectin is an epidermal plakin protein and is a component of hemidesmosome [34]. In the epidermis, the N-terminal of plectin includes binding sites for the cytoplasmic region of integrin ß4, BP180 and actin filaments and the C-terminal connects to keratin filaments [27]. It plays a key role in linking the keratin filament network to hemidesmosomes at the plasma cell membrane [34]. Mutations in plectin gene lead to various forms of EBS, including EBS associated with muscular dystrophy or with pyloric atresia and EBS-Ogna [27].
\nThe first specific target antigen of circulating autoantibodies identified in bullous pemphigoid patients, 230 kDa bullous pemphigoid antigen, which is also called the bullous pemphigoid antigen (BPAG) 1 isoform e (BPAG1e) is an intracellular, hemidesmosomal protein and a member of plakin family [33].
\nIt is the major component of the hemidesmosomal inner dense plaque [29]. BPAG1e interacts with cytoplasmic domain of type XVII collagen, keratin intermediate filaments, erbin and integrin ß4. It links the keratin intermediate cytoskeleton to multiple hemidesmosome components [32]. The N-terminal of BP230 has a role in the integration of BP230 into the desmosomes and has binding sites for BP180 and ß4 integrin, and the C-terminal has binding sites for intermediate keratin filaments [27].
\nThough BP230 is a major target antigen in BP, the pathogenic relevance of BP230 in BP is not clear due to its intracellular localization [35]. In a study in 1995 in BPAG1e knockout mice, hemidesmosomes were otherwise normal, but they lacked the inner plate and had no cytoskeleton attached. The cell growth or substratum adhesion was also not affected indicating that BPAG1e was not absolutely essential for hemidesmosome or BMZ assembly. The mice also developed severe dystonia and sensory nerve degeneration [36]. In 2014, Feldrihan et al. demonstrated that antibodies against BP230 were nonpathogenic in experimental models of bullous pemphigoid [37].
\nType VII collagen, which is also known as 180-kDa bullous pemphigoid antigen, is a transmembrane collagenous protein which is located within the hemidesmosome and lamina lucida [26, 30]. Its intracellular ligands are plectin, BPAG1e and ß4 integrin, and the extracellular ligands are α6 integrin and laminin 332 [29]. Collagen XVII spans almost the entire length of the BMZ and it is a major component of the hemidesmosome [31]. It is thought to play a role in the structure or stability of anchoring filaments, and it has an important function in maintaining the integrity of dermoepidermal junction [32].
\nAutoantibodies from patients with BP, pemphigoid gestationis (PG) and linear IgA bullous disease (LABD) target the NC16a domain of BPAG2 and from patients with mucous membrane pemphigoid (MMP) tend to target the distal carboxy terminus of BPAG2, which extends deeper into basement membrane as well as NC16A [25].
\nThe ectodomain of BP180 can be proteolytically shed from the cell surface through cleavage within the NC16A domain generating neoepitopes and the resulting 120 kDa fragment is LAD-1 that can be further processed into a 97 kDa fragment, which is targeted in linear IgA disease and also in BP and pemphigoid gestationis [35].
\nMutations in COL17A1 gene encoding type VII collagen cause non-Herlitz subtypes of junctional EB [27].
\nIntegrins are a family of cell adhesion receptors, which have important roles in ligand binding and signaling [11]. The primary integrin in the cutaneous BMZ is α6β4 integrin, which is critical in the adhesion of basal cells to the underlying BMZ [30]. It links the intracellular hemidesmosomal plaque to the extracellular matrix and plays an important role in initiating signaling pathways involved in cell migration, differentiation and survival. The large intracellular domain of β4 integrin interacts with cytoplasmic domain of BP180 and provides linkage to keratin filaments via plectin. The extracellular domain of α6 and β4 integrins provides binding sites for various laminin isoforms, including laminin 332 [27]. Mutations in either α6 or β4 chains result in autosomal recessive junctional EB associated with pyloric atresia [31].
\nAutoantibodies against α6 and β4 integrins have been detected in a subgroup of patients with MMP. Autoantibodies recognizing the α6 subunit were found in patients with oral lesions, and autoantibodies recognizing the ß4 subunit were found in patients with ocular involvement [35].
\nCD151 is a member of the tetraspanin family of cell surface proteins [28]. It is expressed on the basolateral surface of basal keratinocytes concentrated within desmosomes [27, 28]. The possible interaction partners of CD151 are the α3β1 and α6β1 integrins [32]. CD151 is thought to play a role in the organization and stability of hemidesmosomes by facilitating the formation of stable laminin-binding complexes with integrin α6β4 as well as being involved in cellular signaling [27, 28].
\nLaminins are a heterogeneous family of noncollagenous glycoproteins within the lamina lucida/lamina densa of all basement membranes. The laminin molecule is formed by three different polypeptide subunits: α, β and γ [38]. Laminins have a cruciform structure containing both globular- and rod-like segments which are implicated in interactions with other extracellular matrix molecules, like the hemidesmosomal components and type VII collagen, as well as in cell attachment [30]. Laminins are the major components of all the basement membranes along with collagen IV and exist in several isoforms which have been shown to self-assemble into independent networks that are cross-linked by nidogen and perlecan [38]. To date, 16 laminin isoforms have been identified, and some of the laminin isoforms are expressed in the epidermal BMZ [30, 32]. Laminins 5,6 and 10 are the main epidermal BMZ-specific laminins [32]. Laminins promote basement membrane assembly and maintain cell and tissue integrity. Laminins within basement membranes serve as ligands for overlying cell surface receptors, thereby providing signals regarding the epithelial microenvironment [25]. The integrins, a family of cellular receptors, are major receptors that mediate cell adhesion to laminins [38].
\nPreviously known as laminin 5, laminin 332 (epiligrin, kalinin, nicein, GB3 antigen, BM600) is the major laminin within the cutaneous BMZ [25, 30]. It consists of α3, ß3 and γ 2 laminin polypeptide chains [26]. It is found at the upper lamina densa/lamina lucida border at the base of anchoring filaments [32]. It plays an essential role in dermal-epidermal attachment and can be regarded as a bridge between hemidesmosomal proteins (α6ß4 integrin and type XVII collagen) and the anchoring fibrils (Type VII collagen) on the dermal site [27, 35].
\nThe mutations in LAMA3, LAMB3 and LAMC2 genes encoding laminin 332 cause Herlitz type of junctional EB [35].
\nAutoantibodies against laminin 332 mainly directed against the α3 chain and can be detected in 20% of patients with MMP. This subgroup is termed anti-laminin 332 MMP, and it is associated with a solid malignancy in 30% of the cases [35].
\nLaminin γ 1 is a component of various laminin heterotrimers, including laminin 311, 321 and 511. It has been described as a target in anti-laminin γ1 pemphigoid, previously known as anti-p200 pemphigoid [35].
\nThe integrin α3 subunit may dimerize with ß1 integrin in the dermoepidermal junction and contribute to epithelial-mesenchymal signaling [27]. Integrin α3 is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment. Muta-tions in the gene for the integrin α3 subunit causes an autosomal recessive multiorgan disorder characterized with interstitial lung disease, nephrotic syndrome and junctional EB [39].
\nNidogens (previously known as entactin) are ubiquitous BM glycoproteins [24, 25]. The predominating nidogen is nidogen-1, and nidogen-2 was discovered as second mammalian isoform [24]. They interact with many other BMZ molecules, in particular with laminin and collagen IV, and their primary function appears to be stabilizing interactions between laminins and collagen IV with the lamina densa [35].
\nNidogens are not required for epidermal BMZ formation because of the overlapping functions of many of the BMZ components [31].
\nType IV collagen is found only in basement membranes and consists of three α-chain subunits which can be identical or genetically distinct but structurally related [25, 31]. Collagen IV’s primary role in the basement membrane is structural, as its three-dimensional lattice superstructure forms the basal lamina [31]. It is linked to laminins 5/6/10 complex by nidogen [32]. Collagen IV also has been associated with angiogenesis, tissue remodeling and cancer progression. There are many genetic diseases attributed to collagen IV, including Goodpasture syndrome, Alport syndrome, diffuse esophageal leiomyomatosis, benign familial hematuria [25].
\nHeparan sulfate proteoglycans are glycoproteins which are found at the cell surface and in the extracellular matrix, where they interact with a plethora of ligands [40]. Characteristically, three proteoglycans are present in vascular and epithelial basement membranes, including perlecan, agrin and collagen XVIII [29]. They are present within, just above and just below the lamina densa of the epidermal basement membrane [25]. They can interact with various components of lamina densa, including type IV collagen and nidogen, and they are believed to contribute to the overall architecture of the basement membrane as well as tissue-specific functions [25, 29]. Their high sulfate charge contributes to the negative charge of basement membranes and restricts the permeability of these matrices [25].
\nType VII collagen is the major component of anchoring fibrils, and it provides mechanical strength by linking the basal lamina and the underlying connective tissue [35]. Anchoring fibrils lie beneath the basal lamina, and they are fan-like, cross-banded structures extending into the papillary dermis that form semicircular loops [32]. They extend from the lower part of the lamina densa to the upper reticular dermis [25].
\nType VII collagen consists of three identical α-chains that self-organize into a triple-helical collagenous structure. Each triple helical domain is flanked by a noncollagenous N-terminal and a C-terminal [27]. It contains a large globular noncollagenous domain termed NC1 in the amino terminal and a smaller domain termed NC2 in the carboxy terminal [25].
\nA large number of type VII collagen molecules laterally aggregate to form anchoring fibrils in which NC1 domains bind the lamina densa at one end and either loop back into lamina densa or else connect to anchoring plaques in sublamina densa region [25, 30]. The anchoring plaques are electron-dense structures which contain collagen IV and laminin 332 [29]. Specific subdomains within the NC1 domains have affinity for type I fibrillar collagen in the dermis and type IV collagen in the lamina densa and anchoring plaques. It also interacts with laminin 332 [25].
\nThe importance of anchoring fibrils in securing the adhesion of the dermal-epidermal basement membrane to the underlying dermis is seen in mutations in COL7A1 encoding type VII collagen which underlie both autosomal dominant and autosomal recessive forms of dystrophic EB in which the blister formation occurs in the sublamina densa region [34].
\nIgG autoantibodies directed against type VII collagen also results in epidermolysis bullosa acquisita which is a severe, acquired autoimmune bullous disease [41].
\nType VII collagen has also been described as autoantigen in a small subgroup of patients with MMP, bullous systemic lupus erythematosus and LABD [35] (Table 3).
\nBasement membrane zone molecules | \nAcquired subepidermal blistering disease | \n
---|---|
BPAG1e | \nBullous pemphigoid Mucous membrane (cicatricial) pemphigoid Pemphigoid gestationis Linear IgA disease Lichen planus pemphigoides | \n
Collagen XVII | \nBullous pemphigoid Pemphigoid gestationis Mucous membrane (cicatricial) pemphigoid Lichen planus pemphigoides Linear IgA disease | \n
Laminin 332 | \nMucous membrane (cicatricial) pemphigoid associated with malignancy | \n
Laminin 311 | \nMucous membrane (cicatricial) pemphigoid | \n
Laminin γ1 | \nAnti-laminin γ1 pemphigoid, (anti-p200 pemphigoid) | \n
Integrin α6β4 | \nMucous membrane (cicatricial) pemphigoid | \n
Type VII collagen | \nEpidermolysis bullosa acquisita Bullous lupus erythematosus | \n
Targeted molecules and the corresponding acquired subepidermal blistering disease.
As renewable and biodegradable nanomaterials, nanocelluloses have raised a huge interest for several decades. Indeed, their natural available and abundant source—the biomass—as well their interesting properties makes them materials of choice for new nanomaterial science in a large panel of applications. Two types of nanocelluloses exist: cellulose nanofibrils (CNF) and cellulose nanocrystals (CNC) differing from each other in their properties as well in their isolation process. As presented in Figure 1, the exponential evolution of the number of publications and patents dealing with cellulose nanocrystals confirms the large interest generated by these nanomaterials.
Noncumulative evolution of the number of publications and patents dealing with CNC (source: SciFinder, April 2019—Descriptors, cellulose nanocrystal, cellulose nanorod, rodlike cellulose, cellulose nanowire, cellulose crystallite, cellulose nanoparticle, cellulose whiskers, nanocrystalline cellulose—Language, English).
This chapter aims to describe CNC isolation from cellulose using classical or more recent methods, as well as their properties and applications.
Cellulose can be extracted from a large variety of sources, kike wood (the main source), seed fibers (cotton), bast fibers (flax, jute, ramie), some animal species (tunicates), fungi, and fruits, with different cellulose contents [1]. With more than 1011 tons of cellulose produced each year [2], with less than 5% is extracted for applications, cellulose is the most abundant polymer on our planet [3]. Historically, cellulose was discovered after being extracted with nitric acid from several plants by the French researcher Anselme Payen in 1838, who characterized the residual compound with chemical formula C6H10O5 [3, 4]. In 1939, the name “cellulose” was for the first time introduced in the scientific community. After almost 200 years of cellulose extraction, modification, and industrial use, this sustainable and biodegradable polymer is currently used for several applications, from paper and cardboard to biomedical, building, textile, cosmetics, pharmacy, and composites [5, 6]. Indeed, intrinsic properties of cellulose fibers—abundancy, renewability, and availability—as well its fibrillary structure or mechanical properties (strength, flexibility) make them materials of choice for such applications. Indeed, in their natural form, cellulose fibers are included in hemicellulose- and lignin-based matrix like a natural composite and acts as the primary compound of plant cell walls by providing high mechanical properties and maintaining their structure.
Looking more precisely at cellulose structure, it is a linear homopolymer of β-D-glucopyranose (C6H12O6) units. These anhydro-D-glucose units (AGU) are linked by β-(1–4)-glycosidic linkage, a covalent bonding between equatorial OH group in C4 and C1 carbon atom of the next unit. Every unit is twisted at 180°C with respect to its surrounding environment and is in chair conformation, with the three hydroxyl groups in equatorial position. Cellobiose (C12H22O11)—the combination of two anhydroglucose units (AGU)—is the repeating unit of cellulose [2, 3]. Cellulose general formula is represented in Figure 2(a).
(a) Chemical structure of cellulose chain and (b) representation of some hydrogen bonds between two cellulose chains.
End groups of cellulose polymer are chemically different: one nonreducing end and one reducing bearing aldehyde group. Note that cellulose degree of polymerization (DP) is expressed as a function of the AGU unit number and depends on the cellulose source and isolation process (e.g., DP between 300 and 1700 for wood pulp and 800–1000 for cotton) [3]. The numerous hydroxyl groups—three per AGU—induce possible functionalization of cellulose as well as intra- and intermolecular hydrogen bonds in and between cellulose chains. These interactions form stabilized and flexible cellulose filaments: the cellulose microfibrils (see Figure 3(a)).
Schematization of a simplified (a) composition of cellulose fiber (extracted and adapted from [7]) and (b) arrangements of crystalline and amorphous domains in cellulose chains (extracted from [8]).
Moreover, cellulosic chains are rearranged into different regions: the ordered crystalline and the disordered amorphous ones. Indeed, a cellulose chain can be represented as a crystalline wire connected by amorphous areas (see Figure 3(b)). It explains the aggregation of cellulose chains and thus their arrangement into microfibrils. The latter are assembled in bundles, themselves assembled in cellulose fibers, with a semi-crystalline structure. Cellulose crystals present four polymorphs: cellulose I, II, III, and IV. Cellulose I is the most abundant form in nature and is present under cellulose Iα and Iβ forms whose ratio depends on the source and affect cellulose properties [3, 4]. Crystallinity of cellulose varies according to the source and is in the large range of 40–80% [3], leading to highly cohesive fibers. Looking more precisely at the level of the microfibrils, they are composed of elementary fibrils, with a diameter around 5 nm. This general structure provides visualization of the different scales inside the cellulose fiber. In addition to being environmentally relevant, cellulose fibers present interesting mechanical properties, ability for further surface modification, low toxicity, low cost, and other properties making them outstanding materials for a lot of traditional as well as innovative applications.
Hierarchical structure of cellulose fibers is at the origin of cellulosic nanomaterials, the nanocelluloses, having at least one dimension of nanometric scale as their name suggests. Indeed, from elementary fibrils, two types of nanocellulose can be obtained differing by their isolation procedure, as well by their properties and applications. Figure 4 shows their different morphologies. Briefly, cellulose nanofibrils are obtained by applying high shear mechanical treatment to a cellulose suspension, and recovered nanofibrils have a length between 500 nm and 10 μm and a width between 5 and 50 nm, according to their preparation method, their source, and potential chemical treatment.
TEM images of (a) microfibrillated cellulose (MFC), (b) TEMPO-oxidized nanofibrillated cellulose (NFC), and (c) wood cellulose nanocrystals (CNC) (extracted from [8]).
First investigation on cellulose nanocrystal (CNC) was reported by Ranby et al. in 1950 [9, 10]: after carrying out a sulfuric acid hydrolysis to wood cellulose fibers, he observed rodlike particles with two nanoscale dimensions. Indeed, by hydrolyzing cellulose fibers, most of the amorphous parts of the cellulose are disintegrated, and final nanomaterials are highly crystalline. Cellulose nanocrystals have a length between 100 and 500 nm and a width between 2 and 15 nm depending on the cellulose source and the chemical treatment applied. Indeed, even if the use of sulfuric acid for hydrolysis is the most common process, other research groups have investigated the use of other acids, leading to CNC with different properties. In any case, washing steps are essential to remove any chemicals and to well-disperse the CNC. Concerning their industrialization, around 10 CNC producers can be recorded, with annual production up to 400 tons/year. These productions are significantly lower than those of CNF, but requirement of more chemicals and difficult industrial production steps (washing, dialysis, and sonication) can easily explain this difference. Table 1 shows the non-exhaustive list of CNC producers and their annual production capacity. Note that the leader and pioneer CelluForce© has recently announced new strategy of efficient industrialization [11].
Company | Country | Annual production capacity (tons) |
---|---|---|
CelluForce Inc. | USA | 400 |
America Process Inc. (GranBio) | USA | 200 |
Alberta Pacific Forest Industries Inc. | Canada | 180 (expected in 2021) |
Anomera Inc. | Canada | 11 |
Forest Products Laboratory (FPL) | USA | 5 |
University of Maine | USA | 4 |
Blue Goose Biorefineries Inc. | Canada | 4 |
Cellulose Lab | Canada | 4 |
Advanced Cellulosic Material Inc. | Canada | 1 |
FPInnovations | Canada | 0.5 |
InnoTech Alberta | Canada | 0.3 |
Embrapa/National Nanotechnology Laboratory for Agriculture | Brazil | Pilot |
Melodea | Israel | Pilot |
Cellulose nanocrystals are obtained by applying a chemical treatment to cellulose fibers: mild acid hydrolysis. Typically employing strong sulfuric acid H2SO4 is going to penetrate into accessible amorphous domains of cellulosic chains and dissolve them to release crystalline parts. Amorphous domains are randomly oriented and arranged inducing a lower density of these domains which are thus more vulnerable to acid hydrolysis [14] and especially to the infiltration of hydronium ions H3O+ leading to hydrolytic cleavage of glycosidic bonds. In this sense, Ranby et al. were the first to prove the preparation and the presence of CNCs, the smallest cellulosic building blocks. Figure 5 synthesizes the different steps of CNC isolation using sulfuric acid hydrolysis.
Schematic representation of sulfuric hydrolysis of cellulose fibers (This scheme was extracted from an unpublished work (PhD manuscript of E. Gicquel, 2017)).
As previously mentioned, cellulose fibrils are exposed to a sulfuric acid hydrolysis, with defined concentration, temperature, and reaction time. Once amorphous domains are dissolved, a sonication step allows the separation between intact crystalline domains, leading to isolated CNC bearing half-sulfate ester groups on their surface. These charges come from the reaction between sulfuric acid and surface hydroxyl groups of cellulose and induce repulsive forces between negatively charged CNC leading to colloidal stability and dispersion in water [15]. While sulfuric acid is the most common acid used for cellulose fibers hydrolysis, other researches have focused on the use of other organic or mineral acids, like phosphoric acid, hydrobromic acid, or hydrochloric acid [16, 17, 18, 19], generally leading to less stable suspension due to the lack of charges at the surface of the CNC. Moreover, the use of deep eutectic solvents is the subject of the next part of this chapter. When cellulosic source is not totally pure, previous steps are required. Indeed, alkali treatment (generally NaOH) and bleaching steps (generally acetic acid, aqueous chlorite) are essential to remove impurities, especially lignin and hemicelluloses when starting directly from biomass or even biowaste. Cellulose content of raw material is thus drastically increased. Note that a lot of studies have investigated the production of CNC from less conventional sources like rice, soy, and others in order to valorize food and organic waste [20, 21]. Final yield and morphology of CNC are really dependent on the cellulosic source and on the hydrolysis conditions. Indeed, optimization and control of the acid hydrolysis have been the subject of several publications. If common parameters are the hydrolysis with 64 wt% sulfuric acid at 40–45°C during about 30 min, it has been proved that variation of one of the parameters can largely influence the reaction yield as well as CNC properties. For example, by increasing of 10 min the time of hydrolysis, it has been shown by Flauzino Neto et al. that crystalline parts are destructed inducing a significant decrease in length [20]. Beck et al. [22] have confirmed this point, admitting that too long times of reaction induce degradation of cellulose but that too short times induce only large and non-dispersible fibers and large aggregates. Only specific reaction times yield to a well-dispersed colloidal suspension of CNC. Chen et al. [17] have confirmed that best yield and CNC properties are obtained with previously mentioned standard conditions. Moreover, the importance of acid concentration relative to cellulose fibers is highlighted too, since a too high concentration could be too drastic and a too low concentration insufficient for the hydrolysis efficiency. At the end of the reaction, mixture media are first diluted with distilled water to quench the reaction, then submitting to several separation steps with centrifugation cycles and filtrations and washed by dialysis against distilled water for several days, in order to remove unreacted compounds and chemicals. In some cases, they use also NaOH to neutralize pH which can modify the crystallinity and the surface ions. After dialysis, a final centrifugation cycle or another filtration process aims to remove aggregates. CNC suspension is finally sonicated in order to well disperse the nanocrystal and obtain colloidal suspension thanks to dimensions and sulfate half ester groups bearing by CNC.
In addition to their nanometric size, CNC are unique biodegradable and renewable nanomaterials. Moreover, they result from a previously described optimized acid hydrolysis applied on abundant sources of cellulose and exhibit many other interesting properties. Figure 6 summarizes the main CNC properties as well as their applications. Regarding the surface properties of CNC, they generally exhibit half-sulfate ester groups (▬SO3−) on their surface after being treated with sulfuric acid. Even if the amount of ▬SO3− is pretty low (about 50–200 μmol g−1), these negative charges are sufficient to induce repulsive forces between nanomaterials and thus colloidal stability in aqueous media. Moreover, as presented in Figure 6, due to isolation process, other charged groups can be present on CNC surface, like carboxyl groups (▬COO−), aldehyde groups (▬CHO), and others [23], leading to different charge properties inducing different CNC properties. Moreover, numerous hydroxyl groups (three groups in each AGU units) are at reactive surface sites for the introduction of new functional groups via hydroxyl groups’ functionalization. Regarding the physical properties of CNC, they have a low density (1.606 g cm−3), a high aspect ratio length/width (e.g., varying between 10 and 30 for CNC extracted from cotton and around 70 for those extracted from tunicate [15]), and a high surface area (between 150 and 800 m2 g−1). Note that all their morphological and surface properties are highly dependent on their source as well as their isolation process and conditions [8, 22]. Moreover, CNC exhibit highly interesting mechanical properties. Indeed, in addition to their high crystallinity (between 54 and 88% according to the source [24]), their high elastic modulus (≈150 ± 50 GPa) and tensile strength (≈7.5 ± 0.5 GPa) [25] make them interesting materials as mechanical reinforcement in polymer matrices, for example. For comparison, their mechanical properties are similar to Kevlar® fibers [26] widely used in composite field.
Main surface and physical properties of cellulose nanocrystals and inherent main applications.
At low solid content (<3 wt%), due to hydrogen bonds between cellulose chains and thus between each nanocrystals, CNC water suspension is in the form of a translucent gel. Rheological properties of CNC are outstanding and concentration dependent. Indeed, at low concentration (<3 wt%), CNC suspension presents shear thinning behavior at high shear rate, and at higher concentration (>3 wt%), the suspension presents shear thinning behavior explained by the nanocrystals alignment in the flow direction at a critical shear rate [27]. Source and isolation of CNC influence these rheological properties too. Besides all these properties, CNC self-organize in ordered structure, especially to form a nematic phase. Revol et al. [28] described in the 1990s this self-organization of CNC in water suspension into stable chiral nematic phases. These last exhibit liquid crystalline properties, which when added to intrinsic birefringence of CNC induce interesting optical properties. Moreover, when ordered CNC suspension is solvent evaporated and thus solidified in a self-standing film, conserved chiral nematic structure (helicoidal structures) and iridescent behavior of films are observed and monitored by CNC concentration and surface charge as well as suspension sonication [27, 28]. Figure 7 shows explicit pictures of these rheological and liquid crystalline properties.
(a) Translucent gel-like CNC suspension at 15 wt% in water (extracted from 57), (b) birefringence with shear-inducing observed for an aqueous CNC suspension at 0.6 wt% in cross-polarized light (extracted from [57]), (c) solvent-casted CNC film in diffuse light, normal to the surface (on the left part) and oblique to the surface (on the right part) (extracted from [29]), and (d) schematic representation of CNC orientation in isotropic and anisotropic phases (This scheme was extracted from an unpublished work (PhD manuscript of R. Bardet, 2014)).
All these outstanding surface and physical properties of CNC confirm their high and increasing interest in research and industrial field during the last decades. Although their isolation and characterization are currently well-advanced and optimized, application fields are at the center of ongoing researches, as described in the following part.
As exposed in Figure 6, CNC found applications in various fields. Indeed, thanks to their outstanding morphological, mechanical, and rheological properties as well as their colloidal stability and high surface reactivity. All these properties added to their biodegradability and renewability make them highly interesting and innovative materials with many potential applications. Table 2 summarizes CNC applications and corresponding exploited properties, as well as some literature references.
Market | Applications | Exploited CNC properties | References |
---|---|---|---|
Composites/films | Nanocomposites Flexible packaging Optical films | High mechanical properties Filmogenic properties Morphology | [30, 31] |
Coatings/paints/adhesives | Coatings for flexible packaging | Morphology Rheological properties | [32, 33] |
Electronics/sensors | Flexible electronics E-paper Piezoelectric sensors | Electrical insulating Piezoelectric properties Surface area | [34, 35, 36] |
Filtration | Mesoporous films and membranes | High specific surface area High mechanical properties Hydrophilicity | [37] |
Biomedical | Biocomposites for bone/tooth replacement Drug delivery Protein immobilization Wound dressings Biosensors | Low toxicity Colloidal stability High mechanical properties Surface reactivity | [38, 39] |
Energy | Supercapacitors Flexible batteries | Strength Large surface area | [40] |
Cosmetics | Hydrogels and foams | Colloidal stability Emulsion interfacial stabilization | [41, 42] |
Security | Security papers and inks | Iridescent properties Morphology | [43] |
Main market applications of CNC and corresponding properties and literature references.
Nanocomposite field is an emerging research area which finds applications in several domains like food packaging, medical devices, and building. Renewable aspect of CNC is particularly interesting since it correlates with the development of bio-based and biodegradable polymers as mentioned in the first part of this chapter. Moreover, these same properties are just as interesting in other application fields, from coatings, electronics, filtration, and biomedical devices to energy, cosmetics, and security. Note that for applications that may enter in contact with food or human body and for any industrialization, toxicity of CNC is a key challenge to investigate. Indeed, even if cellulose is known to be a nontoxic polymer, CNC are nanomaterials—and the “nano” prefix can be frightened for media and population—with specific morphology and surface properties. A recent review of Roman et al. [44] explored CNC toxicity. Results of this study correlate with previous results of Lin et al. [39] and Kovacs et al. [45], demonstrating that CNC are not toxic by ingestion or dermal contact and for aquatic organisms. However, pulmonary and cytotoxicity are less ideal since their toxicity depends on CNC properties and form (especially if they are in powder form, since they are more volatile). In any case, toxicity of CNC is low, especially when they are in wet-state or in composites, films, or coatings, for example, not constraining development of new CNC-based products.
As described in the first part of this chapter, the traditional methods used to obtain cellulose nanocrystal consist of strong acid hydrolysis, enzymatic hydrolysis, or oxidation reactions. These treatments allow to hydrolyzing the amorphous regions in cellulose chains, and they are often followed by mechanical or ultrasonic treatment to homogenize the suspension. However, these methods use toxic chemicals and are difficult to industrialize.
Deep eutectic solvents (DESs) are a new class of green organic solvents; they are in the continuity of molten salt and ionic liquid solvent, but they are less toxic and easier to use. A deep eutectic solvent is composed of at least two compounds, a Lewis or Brönsted acid and a base. According to its constituents, a DES can be classed in one of the four existing categories listed in Table 3.
Type | Component 1 | Component 2 |
---|---|---|
I | Quaternary ammonium salt | Metal chloride |
II | Quaternary ammonium salt | Metal chloride hydrate |
III | Quaternary ammonium salt | Hydrogen bond donor |
IV | Metal chloride hydrate | Hydrogen bond donor |
The four DES families.
The association of these compounds with a specific ratio forms an eutectic mixture with a melting temperature far below than of its constituents.
In the case of type III, it is accepted that the self-association occurs via hydrogen bonding interactions between the hydrogen bond donor and the hydrogen bond acceptor. The strong hydrogen bonds between the different compounds prevent the crystallization of each product and decrease the melting point of the mixture below room temperature [46]. Type III DESs are easy to obtain by simply mixing the compounds with the right ratio at a temperature higher than the melting point during 1 h. The mixture obtained is homogenous and transparent and has a low vapor pressure. However, the main drawback of deep eutectic solvents is their price. Nevertheless, some studies show that it is possible to recycle them between three and five times depending on the DES components and the usage [47]. Moreover, a subclass of DESs, named natural deep eutectic solvents (NADES), is formulated using bio-based compounds; these solvents are environmentally friendly and their price can be lower.
DESs and NADES can be helpful in organic chemistry; indeed they can replace some toxic organic solvents; Zdanowicz summarized all their possible application domains for polysaccharide processing [48]. Among all these applications, one of them consists of the use of type III DESs as an acidic hydrolytic solvent for cellulose nanocrystal obtention.
This principle has been studied for the first time by Sirviö et al. [49]; they manage to extract individual nanocrystals using a choline chloride: oxalic acid dihydrate treatment from dissolving pulp. Different DESs had been prepared in different ratios and studied to hydrolyze the amorphous part of cellulose fibers from different sources: an overview of these treatments is summarized in Table 4.
Cellulose source | Pretreatment (DES, etc.) | Molar ratio | Time | Temp. (°C) | Yield (%) | Dimension (nm) | References |
---|---|---|---|---|---|---|---|
Dissolving pulp | ChCl:OAD | 1:1 | 2 h | 100 | 68 | l = 390 ± 25 d = 13.6 ± 1.1 | [49] |
1:1 | 2 h | 120 | 73 | l = 353 ± 16 d = 13.8 ± 0.7 | |||
ChCl:p–t | 1:1 | 2 h | 60 | 70 | |||
ChCl:levulinic acid | 1:2 | 2 h | 100 | 88 | |||
Dissolving pulp | ChCl:OAD | 1:1 | 30 min | 100 | l = 50–350 d = 3–8 | [50] | |
Cotton fiber | ChCl:OAD | 1:1 | 1 h | 100 | 79.8 | l = 194.1 d = 9.6 ± 2.9 | [51] |
ChCl:OAD | 1:2 | 1 h | 100 | 80.0 | l = 152.7 d = 6.1 ± 1.2 | ||
ChCl:OAD | 1:3 | 1 h | 100 | 81.6 | l = 122.4 d = 4.7 ± 2.2 | ||
Cotton fiber | ChCl:OAD Microwave assisted | 1:1 800 W | 3 min | 80 | 74.2 | l = 100–350 d = 3–25 | [52] |
1:1 800 W | 3 min | 90 | 62.4 | ||||
1:1 800 W | 3 min | 100 | 57.8 | l ≈ 150 d < 17 | |||
Bleached eucalyptus kraft pulp | ChCl:OAD + catalysis, FeCl3.6H2O (mmol/gDES) | 1:4 0 | 7 h | 80 | 86 | l = 5152 ± 3328 | [53] |
1:4 0.15 | 6 h | 80 | 73 | l = 270 ± 92 | |||
1:4 0.3 | 6 h | 80 | 71 | l = 258 ± 54 | |||
1:1 0.15 | 6 h | 80 | 88 | l = 5726 ± 3856 | |||
Bleached birch Kraft pulp | AH:glycerol | 1:2 | 10 min | 70 | d = 5.7 ± 1.3 | [54] | |
Empty fruit bunch | ChCl:citric acid | 1:2 | 6 h | 85 | l = 25–37 | [55] | |
Dissolving pulp | GH:APA | 1:2 | 24 h | Room T | 80 | d = 5.6 ± 1.4 | [56] |
Overview of the different DES pretreatments tested for cellulose nanocrystals obtention.
ChCl, choline chloride; OAD, oxalic acid dihydrate; t, toluenesulfonic; AH, aminoguanidine hydrochloride; GH, guanidine hydrochloride; APA, anhydrous phosphoric acid.
In 2016, Sirviö tried three different DESs with choline chloride as hydrogen bond acceptor and oxalic acid (anhydrous or dihydrate), p-toluenesulfonic acid monohydrate, and levulinic acid as hydrogen bond donors [49]. Only DESs composed of choline chloride/oxalic acid dihydrate (ChCl:OAD) with a 1:1 molar ratio are allowed to obtain, after mechanical disintegration and CNC suspension. Different batches were prepared using different times and temperatures (Figure 8(a–d)). Cellulose nanocrystals obtained after 2 h of treatment at 120°C had the highest aspect ratio with a mean length of 353 ± 16 nm and diameter of 9.9 ± 0.7 nm (Figure 8d). The study showed that the final width of CNCs depends on the pretreatment temperature [57].
Transmission electron micrographs of CNCs using DES pretreatment: (a) ChCl:OAD 1:1, 2 h−100°C [49]; (b) ChCl:OAD 1:1, 4 h−100°C [49]; (c) ChCl:OAD 1:1, 6 h−100°C [49]; (d) ChCl:OAD 1:1, 2 h−120°C [49]; (e) ChCl:OAD 1:1, 1 h−100°C [51]; (f) ChCl:OAD 1:2, 1 h−100°C [51]; (g) ChCl:OAD 1:3, 1 h−100°C [51]; (h) ChCl:OAD 1:4 + cat:FeCl3.6H2O (0.15 mmol/gDES), 6 h–80°C [53]; (i) ChCl:OAD 1:4 + cat:FeCl3.6H2O (0.3 mmol/gDES), 6 h−80°C [53]; (j) ChCl:OAD 1:1, 30 min−100°C [50]; (k) microwave-assisted ChCl:OAD 1:1, 3 min−80°C [52]; (l) microwave-assisted ChCl:OAD 1:1, 3 min−90°C [52]; (m) microwave-assisted ChCl:OAD 1:1, 3 min−100°C [52]; (n) guanidine hydrochloride:anhydrous phosphoric acid 1:2, 24 h room temperature [56]; (o) aminoguanidine hydrochloride:glycerol 1:2, 10 min−70°C [54]; (p) aminoguanidine hydrochloride:glycerol 1:2, 10 min −70°C [54].
Ling et al. studied the effect of ChCl:OAD treatment on cellulose nanocrystal structure [51]; three molar ratios were chosen 1:1, 1:2, and 1:3, under two temperatures 80 and 100°C. Cellulose nanocrystals suspensions were obtained in every case (Figure 8(e–g)). Lower crystallinity and lamellar structures were observed for CNCs with lower acid content, and hydrogen bonds were more broken with higher acid ratio (ChCl:OAD = 1:3) during the DES treatment. Moreover, these CNCs obtained were better dispersed and had a higher aspect ratio.
In order to decrease the treatment temperature and increase the CNC yield, Yang et al. proposed to add a catalyst (FeCl3) during the DES treatment [53]. They found out that the optimum conditions for the treatment were 80°C and 6 h using a deep eutectic solvent composed of choline chloride, oxalic acid dihydrate, and FeCl3·6H2O with a molar ratio of 1:4.43:0.1. Cellulose nanocrystals with a length between 50 and 300 nm and a diameter range of 5–20 nm were isolated from eucalyptus kraft pulp with a yield of 90% (Figure 8(h–i)).
Using ChCl:OAD (1:1) DES, Laitinen et al., in 2017, were able to obtain a CNC suspension after 30 min of pretreatment at 100°C and a microfluidizer treatment. The cellulose nanocrystals obtained had a low charged content and could be used as effective oil–water Pickering stabilizers (Figure 8(j)) [50].
In 2017, interesting work was published by Liu et al. [52]. They reported an ultrafast fabrication of CNCs using the DES ChCl:OAD (1:1) assisted by microwave pretreatment. In only 3 min, the CNCs obtained had diameters between 100 and 25 nm and lengths between 100 and 350 nm (Figure 8(k–m)). The yield was 74.2%, and the nanocrystals’ crystallinity was higher than 82%.
Another DES composed of choline chloride and citric acid with a molar ratio of 2:1 allowed Ibrahim et al., in 2018, to hydrolyze lignocellulosic materials and to obtain cellulose nanocrystals [55].
Some deep eutectic solvents can dissolve cellulose; it is the case for the DESs composed of guanidine hydrochloride and anhydrous phosphoric acid (1:2). This solvent was studied by Sirviö to treat dissolving pulp during 24 h and then regenerate it into cellulose nanoparticles [56] (Figure 8n)).
In addition to the hydrolyzation of cellulose amorphous part, some DESs can simultaneously chemically modify the CNC surface. For example, Li et al. obtained cationic nanocrystals using aminoguanidine hydrochloride and glycerol mixture with a molar ratio of 1:2 (Figure 8(o–p)) [54].
The aim of this chapter was to provide an overview of cellulose nanocrystals and their production by various hydrolysis procedure.
Traditionally extracted from multiple cellulose sources via sulfuric acid hydrolysis, these cellulosic nanomaterials are pioneering for a wide range of applications, briefly introduced in this chapter. Such hydrolysis process has allowed the industrialization of this cellulose nanocrystals since 2011. However, in current context, the development of green chemistry is crucial in this research field, and new alternative process are expected.
In order to support this sustainable strategy, the use of natural deep eutectic solvents for the production of cellulose nanocrystals in mild condition has been very recently developed with interesting and encouraging results.
LGP2 is part of the LabEx Tec 21 (Investissements d’Avenir—grant agreement n°ANR-11-LABX-0030) and of PolyNat Carnot Institute (Investissements d’Avenir—grant agreement n° ANR-16-CARN-0025-01).
The authors declare no conflict of interest.
Supporting women in scientific research and encouraging more women to pursue careers in STEM fields has been an issue on the global agenda for many years. But there is still much to be done. And IntechOpen wants to help.
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\n\nWe aim to publish 100 books in our Women in Science program over the next three years. We are looking for books written, edited, or co-edited by women. Contributing chapters by men are welcome. As always, the quality of the research we publish is paramount.
\n\nAll project proposals go through a two-stage peer review process and are selected based on the following criteria:
\n\nPlus, we want this project to have an impact beyond scientific circles. We will publicize the research in the Women in Science program for a wider general audience through:
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